Cancer results from uncontrolled cell proliferation. This excessive proliferation results, at least in part, from deregulated cell division or cell cycle control. Rational design of novel anti-cancer therapeutic agents requires a comprehensive understanding of the cell cycle. The cyclin-dependent kinases (cdks) play a major role in controlling progression through the cell cycle. However, a major gap in our understanding of the cell cycle stems from our lack of knowledge of the major cdk substrates. Through a database search, we identified a putative novel cyclin/cdk2 substrate, termed pHIRA. This protein was selected as a candidate substrate because it contained a consensus cyclin/cdk2 binding sequence and a number of consensus cyclin/cdk2 phosphoacceptor sites. PHIRA is named after its homology to two S. cerevisiae genes, HIR1 and HIR2, that are cell cycle dependent transcriptional regulators of histone gene expressing in yeast. Our preliminary data is consistent with the notion that human pHIRA is an in vivo substrate of cyclin A or E/cdk2 and a transcriptional activator of histone gene expression. The long term goal of this project is to test the proposal that pHIRA is a cell cycle dependent transcriptional regulator of human histone genes, an in vivo substrate of cyclin A or E/cdk2 and that it serves to couple periodic cyclic/cdk2 kinase activity and S-phase specific histone gene transcription. We have preliminary evidence to suggest that as a regulator of a biosynthetic pathway linked to DNA synthesis (histone expression), pHIRA activity is monitored by an S-phase checkpoint whose role is to coordinate S-phase and associated biosynthetic processes. We will test this idea further.